TY - JOUR T1 - L-745,870 Reduces <span class="sc">l</span>-DOPA-Induced Dyskinesia in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Macaque Model of Parkinson's Disease JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 576 LP - 585 DO - 10.1124/jpet.112.195693 VL - 342 IS - 2 AU - Philippe Huot AU - Tom H. Johnston AU - James B. Koprich AU - Ahmed Aman AU - Susan H. Fox AU - Jonathan M. Brotchie Y1 - 2012/08/01 UR - http://jpet.aspetjournals.org/content/342/2/576.abstract N2 - l-DOPA-induced dyskinesia remains an unmet challenge in the treatment of Parkinson's disease (PD). Here, we investigate the potential antidyskinetic efficacy of 3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2,3-b]pyridine (l-745,870), a potent and selective dopamine D4 receptor antagonist with a good toxicology profile and an excellent safety and tolerability record in phase I/II clinical studies, for non-PD indications. Six macaques were rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. After induction of stable and marked dyskinesia, animals were administered acute challenges of l-745,870 in combination with l-DOPA. To guarantee D4 selectivity at the doses used in the study, we determined the plasma, cerebrospinal fluid, and brain levels of l-745,870. Coadministration of l-745,870 (1 mg/kg) and l-DOPA significantly reduced the severity of dyskinesia, by up to 59%, in comparison with l-DOPA alone (P &lt; 0.01). l-745,870 had no effect on the duration of antiparkinsonian benefit (ON-time) (P &gt; 0.05). However, l-745,870 (1 mg/kg) significantly increased the duration of ON-time without disabling dyskinesia (+204%; P &lt; 0.001) and decreased duration of ON-time with disabling dyskinesia compared with l-DOPA alone (−56%; P &lt; 0.01). Brain levels of l-745,870 (∼600 ng/g) were within the range at which l-745,870 provides selective D4 receptor antagonism. Plasma levels were comparable with those demonstrated to be well tolerated in human studies. These data suggest that selective D4 receptor antagonists represent a potential therapeutic approach for l-DOPA-induced dyskinesia. It is noteworthy that l-745,870 has already undergone significant clinical development, has an excellent profile for a therapeutic candidate, and could be advanced rapidly to phase IIa clinical studies for dyskinesia in PD. ER -